This invention relates to pyridines, pyrimidines, purinones, pyrrolopyrimidinones and pyrrolopyridinones, processes for preparing them, pharmaceutical compositions containing them, and methods of using them to treat certain central nervous system (CNS) and other disorders.
CRF antagonists are mentioned in U.S. Pat. No. 4,605,642, issued Aug. 12, 1986, and U.S. Pat. No. 5,063,245, issued Nov. 5, 1991, referring to peptides and pyrazolinones, respectively. CRF antagonists are also described in U.S. Pat. No. 5,962,479, issued Oct. 5, 1999. The importance of CRF antagonists is set out in the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of stress-related illnesses, such as depression, anxiety, headache, irritable bowel syndrome, inflammatory diseases, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, infertility, head trauma, stroke, and stress-induced infections in humans and animals. The use of CRF antagonists for treatment of Syndrome X has also been described in U.S. patent application Ser. No. 09/696,822, filed Oct. 26, 2000, and European Patent Application No. 00309441.4, filed Oct. 26, 2000, which are also incorporated in their entireties herein by reference. Methods for using CRF antagonists to treat congestive heart failure are described in U.S. Ser. No. 09/248,073, filed Feb. 10, 1999, now U.S. Pat. No. 6,043,260 (issued Mar. 28, 2000) which is also incorporated herein in its entirety by reference.
The present invention provides compounds of the formula 
and pharmaceutically acceptable salts thereof, wherein
the dashed lines represent optional double bonds, with the proviso that when the dashed line in C---G represent a double bond, then the dashed line in N(R6)---C does not represent a double bond; and with the proviso that when the dashed line in N(R6)---C represents a double bond, R6 is absent in formula III and the dashed line in C---G does not represent a double bond;
A is xe2x80x94CR7 or N;
B is xe2x80x94NR1R2, xe2x80x94CR1R2R11, xe2x80x94C(xe2x95x90CR2R12)R1, xe2x80x94NHCHR1R2, xe2x80x94OCHR1R2, xe2x80x94SCHR1R2, xe2x80x94CHR2OR1, xe2x80x94CHR1OR2, xe2x80x94CHR2SR1, xe2x80x94C(S)R2, xe2x80x94C(O)R2, xe2x80x94CHR2NR1R2, xe2x80x94CHR1NHR2, xe2x80x94CHR1N(CH3)R2, or xe2x80x94NR12NR1R2;
when the dashed line in C---G represents a double bond, then G is hydrogen, oxygen, sulfur, NH, or N(C1-C4 alkyl);
when the dashed line in C---G does not represent a double bond, then C---G is xe2x80x94C(H)(NH2), CH2, xe2x80x94C(H)(methoxy), xe2x80x94C(H)(ethoxy), xe2x80x94C(H)(O(C3-C4 alkyl)), xe2x80x94C(H)(halo), xe2x80x94C(H)(trifluoromethoxy), xe2x80x94C(H)(methyl), xe2x80x94C(H)(ethyl), xe2x80x94C(H)(C3-C4 alkyl), xe2x80x94C(H)(S(C1-C4 alkyl)), xe2x80x94C(C1-C4 alkyl)(C1-C4 alkyl), cyclopropyl, xe2x80x94C(H)(cyclopropyl), thiomethoxy, xe2x80x94C(H)(NH2), xe2x80x94C(H)(NHCH3), xe2x80x94C(H)(N(CH3)2), or xe2x80x94C(H)(trifluoromethyl);
wherein said cyclopropyl, methoxy, ethoxy, C3-C4 alkyl, and C1-C4 alkyl groups of C---G may optionally be substituted by one OH, methoxy, or trifluoromethoxy, or may optionally be substituted by from one to six fluoro atoms;
Y is CH or N;
Z is NH, O, S, xe2x80x94N(C1-C2 alkyl), xe2x80x94NC(O)CF3, or xe2x80x94C(R13R14), wherein R13 and R14 are each, independently, hydrogen, trifluoromethyl or methyl, or one of R13 and R14 is cyano and the other is hydrogen or methyl, or xe2x80x94C(R13R14) is a cyclopropyl group, or Z is nitrogen or CH and forms; a five or six membered heterocyclic ring fused with R5, which ring optionally comprises two or three further hetero members selected independently from oxygen, nitrogen, NR12, and S(O)m, and optionally comprises from one to three double bonds, and is optionally substituted with halo, C1-C4 alkyl, xe2x80x94O(C1-C4 alkyl), NH2, NHCH3, N(CH3)2, CF3, or OCF3, with the proviso that said ring does not contain any xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94Sxe2x80x94, or xe2x80x94Oxe2x80x94Oxe2x80x94 bonds, and does not comprise more than two oxygen or S(O)m heterologous members;
R1 is xe2x80x94C(O)H, xe2x80x94C(O)(C1-C6 alkyl), xe2x80x94C(O)(C1-C6 alkylene)(C3-C8 cycloalkyl), xe2x80x94C(O)(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94C(O)(C1-C6 alkylene)(C4-C8 heterocycloalkyl), xe2x80x94C(O)(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), xe2x80x94C1-C6 alkyl, xe2x80x94C3-C8 cycloalkyl, xe2x80x94C4-C8 heterocycloalkyl, xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94(C1-C6 alkylene)(C4-C8 heterocycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), or xe2x80x94O-aryl, or xe2x80x94Oxe2x80x94(C1-C6 alkylene)-aryl; wherein said aryl, C4-C8 heterocycloalkyl, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylene, and C1-C6 alkylene groups may each independently be optionally substituted with from one to six fluoro and may each independently be optionally substituted with one or two substituents R8 independently selected from the group consisting of C1-C4 alkyl, xe2x80x94C3-C8 cycloalkyl, hydroxy, fluoro, chloro, bromo, iodo, CF3, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94(C3-C5 cycloalkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94NH(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(R24)(R25), xe2x80x94N(R24)(R25), xe2x80x94S(C1-C4 alkyl), xe2x80x94S(C3-C5 cycloalkyl), xe2x80x94N(C1-C4alkyl)CO(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), CN, NO2, xe2x80x94OSO2(C1-C4 alkyl), S+(C1-C6 alkyl)(C1-C2 alkyl), xe2x80x94SO(C1-C4 alkyl) and xe2x80x94SO2(C1-C4 alkyl); and wherein the C1-C6 alkyl, C1-C6 alkylene, C5-C8 cycloalkyl, C5-C8 cycloalkylene, and C5-C8 heterocycloalkyl moieties of R1 may optionally independently contain from one to three double or triple bonds; and wherein the C1-C4 alkyl moieties and the C1-C6 alkyl moieties of R8 can optionally independently be substituted with hydroxy, C1-C4 alkyl, amino, aryl, xe2x80x94CH2-aryl, xe2x80x94C3-C5 cycloalkyl, or xe2x80x94Oxe2x80x94(C1-C4 alkyl), and can optionally independently be substituted with from one to five fluoro, and can optionally contain one or two double or triple bonds; and wherein each heterocycloalkyl group of R contains from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12;
R2 is hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl, C4-C8 heterocycloalkyl, xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94(C1-C6 alkylene)(C4-C8 heterocycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), aryl, xe2x80x94(C1-C6 alkylene)aryl, or xe2x80x94(C3-C8 cycloalkylene)(aryl); wherein each of the foregoing R2 groups may optionally be substituted with from one three substituents independently selected from chloro, fluoro, and C1-C6 alkyl, wherein one of said one to three substituents can further be selected from bromo, iodo, C1-C6 alkoxy, xe2x80x94OH, xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C6 alkyl), xe2x80x94S(O)(C1-C6 alkyl), xe2x80x94S(O)2(C1-C6 alkyl), S+(C1-C6 alkyl)(C1-C2 alkyl), CN, and NO2; and wherein the C1-C12 alkyl, xe2x80x94(C1-C6 alkylene), xe2x80x94(C5-C8 cycloalkyl), xe2x80x94(C5-C8 cycloalkylene), and xe2x80x94(C5-C8 heterocycloalkyl) moieties of R2 may optionally independently contain from one to three double or triple bonds; and wherein each heterocycloalkyl group of R2 contains from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12;
or where R1 and R2 are as in xe2x80x94NHCHR1R2, xe2x80x94OCHR1R2, xe2x80x94SCHR1R2, xe2x80x94CHR1R2 or xe2x80x94NR1R2, R1 and R2 of B may form a saturated 5- to 8-membered ring which may optionally contain one or two double bonds and in which one or two of the ring carbons may optionally be replaced by an oxygen, S(O)m, nitrogen or NR12; and which carbocyclic ring can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, C1-C4 alkyl, fluoro, chloro, bromo, iodo, CF3, xe2x80x94Oxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94NH(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)CO(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), CN, NO2, xe2x80x94OSO2(C1-C4 alkyl), xe2x80x94SO(C1-C4 alkyl), and xe2x80x94SO2(C1-C4 alkyl), wherein one of said one to three substituents can further be selected from phenyl;
R3 is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy, OCF3, NH2, NH(C1-C2 alkyl), N(CH3)2, xe2x80x94NHCOCF3, xe2x80x94NHCH2CF3, S(O)m(C1-C4 alkyl), CONH2, xe2x80x94CONHCH3, CON(CH3)2, xe2x80x94CF3, or CH2OCH3;
R4 is hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, xe2x80x94(C1-C4 alkylene)(C3-C5 cycloalkyl), xe2x80x94(C3-C5 cycloalkylene)(C3-C5 cycloalkyl), cyano, fluoro, chloro, bromo, iodo, xe2x80x94OR24, C1-C6 alkoxy, xe2x80x94Oxe2x80x94(C3-C5 cycloalkyl), xe2x80x94Oxe2x80x94(C1-C4 alkylene)(C3-C5 cycloalkyl), xe2x80x94Oxe2x80x94(C3-C5 cycloalkylene)(C3-C5 cycloalkyl), xe2x80x94CH2SC(S)O(C1-C4 alkyl), xe2x80x94CH2OCF3, xe2x80x94CF3, amino, nitro, xe2x80x94NR24R25, xe2x80x94(C1-C4 alkylene)xe2x80x94OR24, xe2x80x94(C1-C4 alkylene)Cl, xe2x80x94(C1-C4 alkylene)NR24R25, xe2x80x94NHCOR24, xe2x80x94NHCONR24R25, xe2x80x94Cxe2x95x90NOR24, xe2x80x94NHNR24R25, xe2x80x94S(O)mR24, xe2x80x94C(O)R24, xe2x80x94OC(O)R24, xe2x80x94C(O)CN, xe2x80x94C(O)NR24R25, xe2x80x94C(O)NHNR24R25, and xe2x80x94COOR24, wherein the alkyl and alkylene groups of R4 may optionally independently contain one or two double or triple bonds and may optionally independently be substituted with one or two substituents R10 independently selected from hydroxy, amino, xe2x80x94NHCOCH3, xe2x80x94NHCOCH2C1, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C2 alkyl), xe2x80x94COO(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94CO(C1-C4 alkyl), C1-C6 alkoxy, C1-C3 thioalkyl, cyano and nitro, and with one to four substituents independently selected from fluoro and chloro;
R5 is aryl or heteroaryl and is substituted with from one to four substituents R27 independently selected from halo, C1-C10 alkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C1-C4 alkylene)(C4-C8 heterocycloalkyl), xe2x80x94(C3-C8 cycloalkyl), xe2x80x94(C4-C8 heterocycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, cyano, xe2x80x94NR24R25, xe2x80x94NR24COR25, xe2x80x94NR24CO2R26, xe2x80x94COR24, xe2x80x94OR25, xe2x80x94CONR24R25, xe2x80x94CO(NOR22)R23, xe2x80x94CO2R26, xe2x80x94Cxe2x95x90N(OR22)R23, and xe2x80x94S(O)mR23; wherein said C1-C10 alkyl, C3-C8 cycloalkyl, (C1-C4 alkylene), (C3-C8 cycloalkyl), (C3-C8 cycloalkylene), and (C4-C8 heterocycloalkyl) groups can be optionally substituted with from one to three substituents independently selected form C1-C4 alkyl, C3-C8 cycloalkyl, (C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), C1-C4 haloalkyl, hydroxy, C1-C6 alkoxy, nitro halo, cyano, xe2x80x94NR24R25, xe2x80x94NR24COR25, NR24CO2R26, xe2x80x94COR24, xe2x80x94OR25, xe2x80x94CONR24R25, CO2R26, xe2x80x94CO(NOR22)R25, and xe2x80x94S(O)mR23; and wherein two adjacent substituents of the R5 group can optionally form a 5-7 membered ring, saturated or unsaturated, fused to R5, which ring optionally can contain one, two, or three heterologous members independently selected from O, S(O)m, and N, but not any xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Oxe2x80x94, or xe2x80x94Nxe2x80x94Sxe2x80x94 bonds, and which ring is optionally substituted with C1-C4 alkyl, C3-C8 cycloalkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cyloalkylene)(C3-C8 cycloalkyl), C1-C4 haloalkyl, nitro, halo, cyano xe2x80x94NR24R25, NR24COR25, NR24CO2R26, xe2x80x94COR24, xe2x80x94OR25, xe2x80x94CONR24R25, CO2R26, xe2x80x94CO(NOR26)R25, or xe2x80x94S(O)mR23; wherein one of said one to four optional substituents R27 can further be selected from xe2x80x94SO2NH(C1-C4 alkyl), xe2x80x94SO2NH(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94SO2NH(C3-C8 cycloalkyl), xe2x80x94SO2NH(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SO2NH2, xe2x80x94NHSO2(C1-C4 alkyl), xe2x80x94NHSO2(C3-C8 cycloalkyl), xe2x80x94NHSO2(C1-C4 alkylene)(C3-C8 cycloalkyl), and xe2x80x94NHSO2(C3-C8 cycloalkylene)(C3-C8 cycloalkyl); and wherein the alkyl, and alkylene groups of R5 may independently optionally contain one double or triple bond;
R6 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), or xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), wherein said alkyl and cycloalkyl may optionally be substituted with one hydroxy, methoxy, ethoxy or fluoro group;
or, wherein the compound is a compound of formula II, R6 and R4 can together form an oxo (xe2x95x90O) group or can be connected to form a 3-8 membered carbocyclic ring, optionally containing one to three double bonds, and optionally containing one, two, or three heterologous ring members selected from O, SOm, N, and NR12, but not containing any xe2x80x94Oxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, or xe2x80x94Nxe2x80x94Sxe2x80x94 bonds, and further optionally substituted with C1-C4 alkyl or C3-C6 cycloalkyl, wherein said C1-C4 alkyl substituent may optionally contain one double or triple bond;
R7 is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, xe2x80x94O(C1-C2 alkyl) xe2x80x94O (cyclopropyl), xe2x80x94COO(C1-C2 alkyl), xe2x80x94COO(C3-C8 cycloalkyl), xe2x80x94OCF3, CF3, xe2x80x94CH2OH, or CH2OCH3;
R11 is hydrogen, hydroxy, fluoro, ethoxy, or methoxy;
R12 is hydrogen or C1-C4 alkyl;
R16 and R17 are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy, except that R16 and R17 are not both methoxy or ethoxy;
or R16 and R17 together form an oxo (xe2x95x90O) group;
or R16 and R17 are connected to form a 3-8 membered carbocyclic ring, optionally containing one to three double bonds, and optionally containing from one to three heterologous ring members selected from O, SOm, N, and NR12, but not containing any xe2x80x94Oxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, or xe2x80x94Nxe2x80x94Sxe2x80x94 bonds, and further optionally substituted with C1-C4 alkyl or C3-C6 cycloalkyl, wherein said C1-C4 alkyl substituent may optionally contain one double or triple bond;
R22 is independently at each occurrence selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkylene)(C3-C8 cycloalkyl), and (C1-C4 alkylene)(C3-C8 cycloalkyl);
R23 is independently at each occurrence selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C8 cycloalkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), aryl, xe2x80x94(C1-C4 alkylene)aryl, piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, and thiomorpholine;
R24 and R25 are independently at each occurrence selected from hydrogen, xe2x80x94C1-C4 alkyl, C1-C4 haloalkyl, especially CF3, xe2x80x94CHF2, CF2CF3, or CH2CF3, xe2x80x94(C1-C4 alkylene)OH, xe2x80x94(C1-C4 alkylene)xe2x80x94Oxe2x80x94(C1-C4 alkyl), xe2x80x94(C1-C4 alkylene)xe2x80x94Oxe2x80x94(C3-C5 cycloalkyl), C3-C8 cycloalkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), xe2x80x94(C4-C8 heterocycloalkyl), xe2x80x94(C1-C4 alkylene)(C4-C8 heterocycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), aryl, and xe2x80x94(C1-C4 alkylene)(aryl), wherein the xe2x80x94C4-C8 heterocycloalkyl groups can each independently optionally be substituted with aryl, CH2-aryl, or C1-C4 alkyl, and can optionally contain one or two double or triple bonds; or, when R24 and R25 are as NR24R25, xe2x80x94C(O)NR24R25, xe2x80x94(C1-C4 alkylene)NR24R25, or xe2x80x94NHCONR24R25, then NR24R25 may further optionally form a 4 to 8 membered heterocyclic ring optionally containing one or two further hetero members independently selected from S(O)m, oxygen, nitrogen, and NR12, and optionally containing from one to three double bonds;
R26 is independently at each occurrence selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), xe2x80x94(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), aryl, and xe2x80x94(C1-C4 alkylene)(aryl); and
wherein each m is independently zero, one, or two,
with the proviso that heterocycloalkyl groups of the compound of formula I, II, or III do not comprise any xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94Sxe2x80x94, or xe2x80x94Oxe2x80x94Oxe2x80x94 bonds, and do not comprise more than two oxygen or S(O)m heterologous members.
In one embodiment, the invention provides compounds of formula I or II, wherein R4 is xe2x80x94NHCH2CF3, xe2x80x94CONHNH2, xe2x80x94CONHNHCH3. In another embodiment R4 is xe2x80x94OCF3 or fluoro. In another embodiment R4 is xe2x80x94OCHF2.
In another embodiment, the invention provides compounds of formula I or II, preferably formula I, wherein R4 is xe2x80x94C(O)NR24R25 or xe2x80x94C(O)NHNR24R25. In a preferred embodiment, R4 is xe2x80x94C(O)NR24R25. If R4 is xe2x80x94C(O)NR24R25 or xe2x80x94C(O)NHNR24R25, then R24 and R25 are in a more particular embodiment selected independently from hydrogen and xe2x80x94C1-C4 alkyl. In another embodiment, R4 is xe2x80x94C(O)NH2 or xe2x80x94C(O)NHCH3. In another embodiment, R4 is xe2x80x94C(O)N(CH3)2.
In another more particular embodiment, the invention provides a compound of formula I, or II, preferably I, as defined above, wherein R4 is xe2x80x94C(O)NHCH2(C3-C5 cycloalkyl), xe2x80x94C(O)NH(C3-C5 cycloalkyl), xe2x80x94C(O)N(C3-C5 cycloalkyl)2, xe2x80x94C(O)NR24R25 wherein R24 and R25 form a 4, 5, or 6 membered heterocyclic ring, xe2x80x94C(O)NH(C4-C8 heterocycloalkyl), or xe2x80x94C(O)NH(CH2(C4-C8 heterocycloalkyl)).
In another embodiment, the invention provides a compound of formula I or II, preferably formula I, wherein R4 is xe2x80x94(C1-C4 alkylene)NR24R25. If R4 is xe2x80x94(C1-C4 alkylene)NR24R25, then R24 and R25 are in a more particular embodiment selected independently from hydrogen, xe2x80x94C1-C4 alkyl, xe2x80x94(C1-C4 alkylene)(C3-C8 cycloalkyl), and C3-C8 cycloalkyl.
In another embodiment, the invention provides a compound of formula I or II as defined above, wherein R4 is xe2x80x94OCH2(C3-C5 cycloalkyl), xe2x80x94Oxe2x80x94(C3-C5 cycloalkyl), xe2x80x94SCH2(C3-C5 cycloalkyl), or xe2x80x94S(C3-C5 cycloalkyl).
In another embodiments of the invention, a compound of formula I or II, preferably I, as defined above, is provided, wherein R4 is xe2x80x94COOCH3. In another embodiment of the invention, a compound of formula I or II, preferably I, is provided wherein R4 is xe2x80x94COOCH2CH3.
Another embodiment of the invention provides compounds of formula I or II, preferably I, as defined above, wherein R4 is xe2x80x94OCH3. In another embodiment of the invention, compounds of formula I or II are provided, wherein R4 is xe2x80x94CH3. In another embodiment, R4 is xe2x80x94CH2CH3. In another embodiment R4 is chloro. In another embodiment, R4 is bromo.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CF3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CH2OH.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CH2OCH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CH2OCF3.
In another embodiment of the invention, the compound of formula I or II, preferably I, is as defined above, and R4 is xe2x80x94SCH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94S(O)CH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94S(O)2CH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94C(O)CH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94NR24R25. Preferably, R24 and R25 are xe2x80x94C1-C4 alkyl or hydrogen. In a more particular embodiment, R4 is xe2x80x94NH2, xe2x80x94NHCH3, or xe2x80x94N(CH3)2.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94NO2.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CH(OH)CH3.
In another embodiment, a compound of formula I or II, preferably I, is provided, wherein R4 is xe2x80x94CN.
In another embodiment, the invention provides compounds of formula I, II, or III as defined above, wherein B is xe2x80x94NR1R2, or xe2x80x94NHCHR1R2. If B is xe2x80x94NR1R2, R1 is preferably C1-C6 alkyl, C3-C8 cycloalkyl, or xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), more preferably xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), and R2 is preferably C1-C12 alkyl optionally containing from one to three double or triple bonds and optionally substituted with from one three fluoro atoms. Preferably, B is xe2x80x94N(CH2-cyclopropyl)(CH2CH3) or xe2x80x94N(CH2-cyclopropyl)(CH2CF3).
If B is xe2x80x94NHCHR1R2, then R1 is preferably xe2x80x94C(O)H, xe2x80x94C(O)(C1-C6 alkyl), or xe2x80x94C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with from one to six fluoro atoms or one or two R8 independently selected from xe2x80x94C1-C4 alkyl, hydroxy and xe2x80x94Oxe2x80x94(C1-C6 alkyl), and R2 is preferably xe2x80x94C1-C12 alkyl optionally containing from one to three double or triple bonds and optionally substituted with from one three substituents selected from fluoro and C1-C6 alkyl. Preferably, if B is xe2x80x94NHCHR1R2, then R1 is independently selected from xe2x80x94CH2CH3 and xe2x80x94CF2CH3, and R2 is independently selected from xe2x80x94CH2CH3, xe2x80x94CF2CH3, xe2x80x94CH(OH)CH3, xe2x80x94CH(OCH3)CH3, xe2x80x94C(OH)(CH3)2, and xe2x80x94C(O)CH3. Preferably B is xe2x80x94NHCH(CH2CH3)2, xe2x80x94NHCH(CH2CH3)(CF2CH3), xe2x80x94NHCH(CF2CH3)2, xe2x80x94NHCH(CH(OH)CH3)(CF2CH3), xe2x80x94NHCH(CH(OH)CH3)(CH2CH3), xe2x80x94NHCH(CH(OCH3)CH3)(CH2CH3), xe2x80x94NHCH(C(O)CH3)(CH2CH3), xe2x80x94NHCH(C(O)CH3)(CF2CH3), xe2x80x94NHCH(C(OH)(CH3)2)(CH2CH3), or xe2x80x94NHCH(C(OH)(CH3)2)(CF2CH3).
are preferably, B is xe2x80x94N(CH2-cyclopropyl)(CH2CH3), xe2x80x94NHCH(CH2CH3)2, xe2x80x94NHCH(CH(OH)CH3)(CF2CH3), xe2x80x94NHCH(CH(OH)CH3)(CH2CH3), xe2x80x94NHCH(CH(OCH3)CH3)(CH2CH3), xe2x80x94NHCH(C(O)CH3)(CH2CH3), or xe2x80x94NHCH(C(OH)(CH3)2)(CH2CH3).
In another embodiment of the invention, B is selected from xe2x80x94OCHR1R2, SCHR1R2, xe2x80x94CHR1NHR2, xe2x80x94CHR1N(CH3)R2, xe2x80x94CHR2OR1, and xe2x80x94CHR1OR2.
In another embodiment of the invention, a compound of formula I, II, or III as defined above is provided, wherein R3 is methyl, ethyl, Oxe2x80x94CH3, xe2x80x94OCF3, Cl, Sxe2x80x94CH3, or CF3. Preferably R3 is methyl.
In another embodiment of the invention, a compound of formula III as defined above is provided wherein the dashed line in C---N(R6) represents a double bond, and the dashed line in C---G does not represent a double bond, and C---G is CH2, C(H)(CH3), or C(H)(CH2CH3).
In another embodiment of the invention, a compound of formula III is provided, wherein the dashed line in C---G represents a double bond, and C---G is Cxe2x95x90O, Cxe2x95x90S, or Cxe2x95x90NH, and C---N(R6) is Cxe2x80x94NH or Cxe2x80x94N(C1-C4 alkyl).
In another embodiment of the invention, a compound of formula II as defined above is provided, wherein CR16R17 and CR4R6 are each independently selected from xe2x80x94Cxe2x95x90O, xe2x80x94CH2, xe2x80x94CH(C1-C4 alkyl), xe2x80x94C(C1-C2 alkyl)2, cyclopropyl, xe2x80x94CHOH, xe2x80x94CHOCH3, xe2x80x94C(OCH2CH2), and xe2x80x94C(CH2OCH2).
In another embodiment, a compound of formula II is provided, wherein CR16R17 is selected from xe2x80x94CH2, xe2x80x94CH(C1-C4 alkyl), xe2x80x94C(C1-C2 alkyl)2, cyclopropyl, xe2x80x94CHOH, and xe2x80x94CHOCH3, and CR4R6 is Cxe2x95x90O, CH2, CH(C1-C2 alkyl), or xe2x80x94CHOCH3.
In another embodiment of the invention, a compound of formula I, II, or III as defined above is provided, wherein R5 is optionally substituted aryl or heteroaryl selected from optionally substituted phenyl, thiazolyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, quinazolinyl, quinoxalinyl, pyrazinyl, pyrimidinyl, indazolyl, imidazolyl, furanyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzisoxazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl, benzoxazolyl, benzothiadiazolyl, pyridyl, benzo[1,3]dioxolyl, and 2,3-dihydro-benzo[1,4]dioxinyl.
In another embodiment, R5 is substituted with from one to four R27 selected independently from C1-C4 alkyl, xe2x80x94Oxe2x80x94(C1-C4 alkyl), chloro, bromo, xe2x80x94CH(CH3)(OH), xe2x80x94C(CH3)2(OH), xe2x80x94CH(CH3)(OCH3), xe2x80x94C(CH3)2(OCH3), OCF3, OCHF2, xe2x80x94O-cyclopropyl, xe2x80x94(xe2x80x94CH2-cyclopropyl, xe2x80x94CH(CF3)(OH), xe2x80x94CH(CF3)(OCH3), xe2x80x94C(xe2x95x90O)(CF3), -2-cyclopropyl-1-OH, 1-cyclopropyl-2-OH, 1-cyclopropyl-1-NH2, xe2x80x94O-oxetanyl, xe2x80x94O-tetrahydrofuranyl, cyclopropyl, and xe2x80x94SCH3.
In another embodiment of the invention, a compound of formula I, II, or III as defined above is provided, wherein R5 is phenyl, pyridyl or pyrimidyl, substituted with two or three R27 groups. In a more particular embodiment, R5 is phenyl, substituted with two or three R27 groups.
In another embodiment, a compound of formula I, II or III, preferably I, as defined above is provided, wherein R5 is phenyl, pyridyl or pyrimidyl, substituted with two or three R27 groups selected from halo, xe2x80x94(C1-C4 haloalkyl), xe2x80x94C(O)R24, xe2x80x94OR25, xe2x80x94C(O)NR24R25, and C1-C10 alkyl which is optionally substituted with one to three substituents, preferably one substituent, selected from hydroxy, C1-C6 alkoxy, and xe2x80x94NR24R25. Preferably, each R27 is independently selected from methyl, ethyl, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)CF3, xe2x80x94C(O)CH3, xe2x80x94CH(OH)CH3, chloro, bromo, fluoro, xe2x80x94OCH2CH3, xe2x80x94O-cyclopropyl, xe2x80x94CH2NH2, xe2x80x94CH2NHCH3, xe2x80x94CH2N(CH3)2, xe2x80x94CH2OCH3, and xe2x80x94CH(OCH3)CH3. More preferably, each R27 is independently selected from methyl, ethyl, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, chloro, bromo, and fluoro.
In another embodiment, a compound of formula I, II or III, preferably I, is provided, wherein xe2x80x94 is phenyl and is substituted with two or three substituents R27 independently selected from methyl, chloro, xe2x80x94OCH3, xe2x80x94OCF3, bromo, and xe2x80x94C(O)NH2.
In another embodiment of the invention, a compound of formula I as defined above is provided, wherein Z is O, NH, or NC(xe2x95x90O)CF3. Preferably Z is O.
In a preferred embodiment of the invention, a compound of formula I is provided, wherein Z is O; B is xe2x80x94NHCHR1R2, wherein R1 is preferably xe2x80x94C(O)H, xe2x80x94C(O)(C1-C6 alkyl), or xe2x80x94C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with from one to six fluoro atoms or one or two R8 independently selected from xe2x80x94C1-C4 alkyl, hydroxy and xe2x80x94xe2x80x94(C1-C6 alkyl), and wherein R2 is preferably xe2x80x94C1-C12 alkyl optionally containing from one to three double or triple bonds and optionally substituted with from one three substituents selected from fluoro and C1-C8 alkyl; R5 is R5 is phenyl, pyridyl or pyrimidyl, substituted with two or three R27 groups selected from halo, xe2x80x94(C1-C4 haloalkyl), xe2x80x94C(O)R24, xe2x80x94OR25, xe2x80x94C(O)NR24R25, and C1-C10 alkyl which is optionally substituted with one to three substituents, preferably one substituent, selected from hydroxy, C1-C6 alkoxy, and xe2x80x94NR24R25; and R4 is xe2x80x94C(O)NR24R25. R24 and R25 of xe2x80x94C(O)NR24R25 are in a more particular embodiment selected independently from hydrogen and xe2x80x94C1-C4 alkyl.
In another preferred embodiment of the invention, a compound of formula I is provided, wherein Z is O; B is xe2x80x94NHCHR1R2, wherein R1 of xe2x80x94NHCHR1R2 is preferably xe2x80x94C(O)H, xe2x80x94C(O)(C1-C6 alkyl), or xe2x80x94C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with from one to six fluoro atoms or one or two R8 independently selected from xe2x80x94C1-C4 alkyl, hydroxy and xe2x80x94Oxe2x80x94(C1-C6 alkyl), and wherein R2 of xe2x80x94NHCHR1R2 is preferably xe2x80x94C1-C12 alkyl optionally containing from one to three double or triple bonds and optionally substituted with from one three substituents selected from fluoro and C1-C6 alkyl; R5 is R5 is phenyl, pyridyl or pyrimidyl, substituted with two or three R27 groups selected from halo, xe2x80x94(C1-C4 haloalkyl), xe2x80x94C(O)R24, xe2x80x94OR25, xe2x80x94C(O)NR24R25, and C1-C10 alkyl which is optionally substituted with one to three substituents, preferably one substituent, selected from hydroxy, C1-C6 alkoxy, and xe2x80x94NR24R25; and R4 is xe2x80x94NR1R2, wherein R1 of xe2x80x94NR1R2 is preferably C1-C6 alkyl, C3-C8 cycloalkyl, or xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), more preferably xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl), and R2 of xe2x80x94NR1R2 is preferably C1-C12 alkyl optionally containing from one to three double or triple bonds and optionally substituted with from one three fluoro atoms. Preferably, B is xe2x80x94N(CH2-cyclopropyl)(CH2CH3) or xe2x80x94N(CH2-cyclopropyl)(CH2CF3).
Examples of preferred compounds of this invention are:
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide;
2-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;
2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;
2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-N-dimethyl-nicotinamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1S,2R-1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide; and
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1S,2S-1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;
and pharmaceutically acceptable salts thereof.
Other examples of preferred compounds of the invention are:
2-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;
4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide;
2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinic acid methyl ester;
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester;
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;
2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl ester; and
2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinic acid methyl ester;
and pharmaceutically acceptable salts thereof.
Other examples of compounds of the invention are:
2-(4-bromo-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinic acid;
[2-(4-bromo-2-methyl-phenylamino)4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;
2-(4-chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6, N-dimethyl-nicotinamide;
cyclopropylmethyl-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;
cyclopropylmethyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine; 
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxycarbonyl-propylamino)-6-methyl-nicotinic acid methyl ester;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxycarbonyl-propylamino)-6-methyl-nicotinic acid methyl ester;
3,3xe2x80x2,6xe2x80x2-trimethyl-2xe2x80x2-(2,4,6-trimethyl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,4xe2x80x2]bipyridinyl;
2-(4-chloro-2,6-dimethyl-phenoxy)-6,N-dimethyl-4-(S)-(tetrahydro-furan-3-ylamino)-nicotinamide;
[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(tetrahydro-furan-3-yl)-amine;
2,5,6-trimethyl-4-pyrrolidin-1-yl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine;
(2-pyrrolidin-1-yl-ethyl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;
(tetrahydro-furan-3-yl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;
2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-pyridine -3-carbaldehyde oxime;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(2-pyrrolidin-1-yl-ethyl)-amine;
N-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;
N2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N1,N1-dimethyl-butane-1,2-diamine;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methylamino-propylamino)-6-methyl-nicotinic acid methyl ester;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(3-methyl-butyl)-(2-pyrrolidin-1-yl-ethyl)-amine;
(3,3-dimethyl-butyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(2-pyrrolidin-1-yl-ethyl)-amine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-morpholin-4-yl-amine;
4-(1-ethyl-propoxy)-2-(4-methoxy-2-methyl-phenylamino)-6-methyl-nicotinic acid;
2-(4-chloro-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinic acid;
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinic acid;
N2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin4-yl]-N1-pyridin-3-ylmethyl-butane-1,2-diamine;
N2-[3,6-dimethyl-2-(2,4 ,6-trimethyl-phenoxy)-pyridin-4-yl]-N1-thiazol-2-ylmethyl-butane-1,2-diamine;
2-(2,4-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinic acid;
[2-(4-chloro-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinonitrile;
1-(4-chloro-2-methyl-phenyl)-5-(1-ethyl-propoxy)-7-methyl-1,4-dihydro-2H-3-oxa-1,8-diaza-naphthalene;
4-(1-ethyl-propylamino)-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione;
4-(1-ethyl-propylamino)-2-methyl-7-(2,4,6-trimethyl-phenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;
4-[3-cyano-4-(1-ethyl-propylamino)-6-methyl-pyridin-2-yloxy]-3-methoxy-benzoic acid;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide;
2-(4-chloro-2,6-dimethyl-phenoxy)-N-(1-hydroxymethyl-propyl)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;
and pharmaceutically acceptable salts of the above compounds.
The invention also relates to a pharmaceutical composition for the treatment of (a) a disorder or condition the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or (b) a disorder or condition selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias, including social phobia, agoraphobia, and specific phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies or addictions, including dependencies or addictions to alcohol, cocaine, heroin, benzodiazapines, or other drugs; drug or alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiuretic hormone; obesity; infertility; head trauma; spinal cord trauma; ischemic neuronal damage, including cerebral ischemia, for example cerebral hippocampal ischemia; excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions, including porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, confinement dysfunction in chicken, sheering stress in sheep, and human-animal interaction stress in dogs; muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; hypoglycemia, and Syndrome X in a mammal, including a human, or bird comprising an amount of a compound of the formula I, II or III, or a pharmaceutically acceptable salt thereof, that is effective in the treatment of such disorder or condition, and a pharmaceutically acceptable carrier.
The invention further includes a method for the treatment of (a) a disorder or condition the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or (b) a disorder or condition selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias, including social phobia, agoraphobia, and specific phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies or addictions, including dependencies or addictions to alcohol, cocaine, heroin, benzodiazapines, or other drugs; drug or alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiuretic hormone; obesity; infertility; head trauma; spinal cord trauma; ischemic neuronal damage, including cerebral ischemia, for example cerebral hippocampal ischemia; excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions, including porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, confinement dysfunction in chicken, sheering stress in sheep, and human-animal interaction stress in dogs; muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; hypoglycemia, and Syndrome X in a mammal, including a human, or bird comprising administering to a subject in need of said treatment an amount of a compound of the formula I, II or III or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
The present invention also provides a pharmaceutical composition for and a method of treating a condition comprising administering a compound of I, II, or III, in an amount effective to treat said condition, wherein said condition is selected from the group consisting of: a) abnormal circadian rhythm; b) depression, further wherein a second compound for treating depression is administered, said second compound for treating depression having an onset of action that is delayed with respect to that of said CRF antagonist; and c) emesis. The aforementioned method can practiced according to the information provided in U.S. Provisional Patent Application No. 60/151,183, filed Aug. 27, 1999, which describes treatment of the aforementioned conditions using CRF antagonists in general and which is incorporated herein by reference in its entirety.
The compounds of formula I, II, and III, described herein can also be used to treat forms of heart failure described in U.S. Ser. No. 09/248,073, supra, and can be made into pharmaceutical compositions therefore.
Examples of more specific forms or manifestations of abnormal circadian rhythm that can be treated according to the present invention include, but are not limited to, time zone change syndrome resulting, seasonal affective disorder, shift-work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome resulting from said abnormal circadian rhythm, advanced sleep phase syndrome, or non-24 hour sleep wake disorder resulting from said abnormal circadian rhythm. Moreover, the compound of formula I, II, or III can be combined in the method or pharmaceutical composition for treatment of abnormal circadian rhythm with a second compound that is useful for treating a sleep disorder, for example tachykinin antagonists, agonists for GABA brain receptors, metalonergic compounds, GABA brain receptor agonists, 5HT2 receptor antagonists, and D4 receptor binding compounds. However, other compounds or substances useful for treating a sleep disorder can be combined with a compound of formula I, II, or III. Such methods and compositions are described in greater detail in U.S. Provisional Patent Application No. 60/151,183, supra.
In another embodiment, said condition is depression, and the second compound having delayed action for treating depression is selected from the group consisting of selective serotonin reuptake inhibitors, tricyclic antidepressants, norepinephrine uptake inhibitors, lithium, bupropion, sertraline, fluoxetine, trazodone, and a tricyclic antidepressant selected from the group consisting of imipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, clomipramine, maprotiline, and carbamazepine, and pharmaceutically acceptable salts and esters of the above-recited compounds.
In another embodiment, the condition being treated is emesis, and the method further comprises administering a second compound for treating emesis. The second compound for treating emesis can be selected from, but is not limited to, tachykinin antagonists, 5HT3 antagonists, GABA agonists, and substance P inhibitors. More specific categories of emesis encompassed in the present invention include emesis induced by a condition or agent selected from the group consisting of pregnancy, vestibular disorder, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, migraine, change in intercranial pressure, chemotherapy, radiation, toxins, and opioid analgesics.